Chapter 10 Alcohol and RA 116
Wieb Patberg 1986 Brandganzen Ets 37/50
Chapter 11
General discussion
Chapter 11 General discussion 118
The studies described in this thesis are based on accurate long-term
monitoring of several weather and RA variables. All data obtained from
1983 till 2004 are plotted in Figure 1. In the earlier years (1983-1989),
the daily joint pain score was the only RA variable that was determined.
Although this is a subjective variable, in retrospect it always reflected
the pain as it was experienced during the past weeks or months. Since
1989, the ESR was determined regularly in order to have an objective
disease variable available. From 1996 on, 2 additional laboratory variables (CRP and RF) were determined more often than before. From
March 1999 till February 2003, with intervals of 14 days, the ESR, CRP
and RF determinations were alternately done at 2 different laboratories,
i.e. about once a month at each laboratory. Although the long-term
trend is comparable, the RF curves were at clearly distinct levels (Figure
1, third trace from top). Moreover, the upper curve (lab A, white circles)
is very irregular with respect to the lower one (lab B, black and green
circles). In general, the ESR and CRP values determined by the two
laboratories were comparable. All RF and ESR values used in the study
described in Chapter 8 were determined by laboratory B. Pooling the
data from both laboratories would have considerably diminished the
correlation of the RF as well as the ESR with the daily time spent outdoors. The ESR values from both laboratories were pooled in the studies described in Chapters 7, and 9.
During the first years of the disease (1979-1991), medication was unstable. The daily dosage of nonsteroidal antiinflammatory drugs (NSAIDs)
was dependent on the intensity of pain (cf. Chapter 4, Figure 1). In this
way, the variation in pain was reduced, and it was rather the medication
that reflected the disease activity than the pain score. From 1992 on, the
use of NSAIDs was kept very stable in order to make the daily joint
pain score more reliable as an indicator of the disease activity (January
1992-June 2001: 75 mg indomethacin daily; from June 2001 on: 25 mg
rofecoxib daily). Probably, due to the stable NSAID dosage the day-today fluctuations in pain score after 1992 were higher than before (Figure
1, bottom trace).
From 1992 till 2004, the dosage of disease-modifying antirheumatic
drugs (DMARDs) was changed only 6 times (pink bar, Figure 1, bottom). The use of azathioprine did not result in a decrease of the ESR. At
a daily dosage of 125 mg, a gradual decrease of the pain score was
Chapter 11 General discussion 119
Effects of medication
Figure 1 Plot of relevant variables related to the author during 21.5 years (1983 till June 2004)
24 h outdoor temperature
Trace 1
The temperature was measured by the Royal Dutch Meteorological Institute (KNMI) at
the location Groningen Airport. The data are available at http://www.knmi.nl /product/.
In the Netherlands, the shape of this curve is almost identical to that of the outdoor vapor
pressure curve (cf. Chapter 4, Figure 1). Corrections for stays abroad are given in Chapter 4.
24 h time spent outdoors
Trace 2
Data represent the total of all periods spent outdoors within 24 h. In general, outdoor
activities were light (mostly sitting and cycling) and at temperatures higher than 0-5 °C no
coat was worn.
Reumatoid factor (RF)
Trace 3
The RF was determined by 2 different laboratories. Due to considerable differences in
reported values, the data were plotted in different curves: lab A (pink circles), and lab B
(black and green circles). Green circles indicate a value <20 IU/ml.
C-reactive protein (CRP)
Trace 4
The single high value in 2000 is related to joint surgery. The elevation in 1997 preceded
the first joint surgery in that year. Pink circles: lab A; black circles: lab B.
Erythrocyte sedimentation rate (ESR)
Trace 5
Elevations in 1997 and 2000: as mentioned for CRP. The single high value in 2001 is
related to joint surgery. Pink circles: lab A; black circles: lab B.
Chapter 11 General discussion 120
Joint punctures and surgery
Symbols
Syringes indicate puncturing of a joint combined with injection of corticosteroids.
Circles marked “JS” indicate days on which joint surgery was performed.
Daily joint pain score
Trace 6
The sum of the pain scores of all 21 (groups of) joints as mentioned in Chapter 1.
Disease-modifying antirheumatic drugs
aza: azathioprine, sal: sulfasalazine (daily dosages in mg), MTX: methotrexate (weekly
dosage in mg).
DMARD
2
24 h outdoor temperature
(°C)
24 h time outdoors
(min)
1
30
20
10
0
-10
-20
360
300
240
180
120
60
0
100
3
RF
(IU/ml)
80
60
40
20
0
60
4
CRP
(mg/ml)
50
40
30
20
10
0
40
35
5
ESR
(mm/h)
30
25
20
15
10
5
6
daily joint pain score
0
60
JS
JS
JS
JS
JS
JS
JS
JS
JS
JSJS
JS
JS
JS
JS
JS
50
40
30
20
10
0
aza
DMARD
1983
1984
1985
1986
1987
1988
1989
sal
1990
aza
aza 50-150
1991
1992
azathioprine 100
1993
1994
MTX 7.5
azathioprine 125
1995
1996
1997
1998
1999
2000
MTX 10
2001
MTX 15
2002
2003
2004
observed (1996-1999). However, this may also be attributed to the periods with increased time spent outdoors as illustrated by the cross correlation in Figure 2 (black circles). The strong decrease of the pain score
as well as the ESR in the summer of 1992 is a nice example of this effect. The transition from azathioprine to methotrexate (MTX) was associated with a decrease of the ESR, CRP, and the pain score, not the RF.
Later, in 2001, the CRP increased again, although the MTX dosage was
increased. During MTX medication, the ESR showed a light tendency
to decrease. However, variations in ESR in this period (2001-June 2004)
were clearly related to the daily time spent outdoors (r: -0.3; P<0.05; at
a phase shift of 60 days; 2001-2003).
In RA, it is difficult to speak of a "natural course" of the disease. The
necessary clinical interventions like adjustment of medication, corticosteroid injections into severely inflamed joints, and joint surgery will often disturb such a natural course. Moreover, due to several experiments,
the course of the RA variables is far from "natural" (Figure 1). However,
in the earlier years (1983-1991) the experiments were limited to a few
measures taken to lower the average ambient temperature and vapor
pressure during the night, like keeping the bedroom window open and
not wearing pyjamas (from September 1984 on; cf. Chapters 3-5). The
joint pain score, and later the ESR as well, in these early years were in
general maximal at the end of the summer, and minimal at the end of
the winter (Chapters 3-6, and 9). This is reflected in the positive correlation of the pain score with temperature as well as vapor pressure. From
1985 till 1988 there were many clinical interventions, which are likely to
have reduced the ESR and the pain score in these years (Figure 1, bottom trace). Joint surgery will have had some lowering effect on the pain
score but hardly on the ESR and CRP since the inflammation in the
joints involved was mostly burnt out. The main reasons for surgery were
reduction of pain, and restoring of lost functions.
Effects of daily time spent outdoors
From 1992 on, the relation of the RA variables with the meteorological
weather was often disturbed by outdoor experiments. In general, the RA
variables improved in periods when the daily time spent outdoors was
long (e.g. June-November 2001), while the opposite was associated with
Chapter 11 General discussion 121
"Natural course" of the disease and relationship with season
periods with short daily time outdoors (e.g. November 2001-May 2002).
Despite this "disturbance", the relation of the RA variables with temperature and vapor pressure was often discernible. This is described in
Chapter 7.
The importance of taking the medication into account is illustrated by
the clear decrease of the RA variables during a period with short daily
time spent outdoors (May-November 2000). Here, the beneficial effect
of the transition from azathioprine to MTX prevails over the unfavorable effect of the decreased exposure to the weather.
The disease activity was influenced by the daily time spent outdoors,
not the other way round; the time spent outdoors was not increased as a
result of feeling better. In fact, the decision to start a new period with
high exposure to the weather was often taken in times of increasing disease activity (e.g. May 2002). Since the alleviation during the long outdoors period in the summer of 1992, I considered being outdoors as an
essential part of my therapy. Further, cross correlation revealed that the
changes in RA variables lagged behind changes in time spent outdoors.
In Figure 2, this is illustrated for the RA variables ESR and joint pain
score (1997-2003). As in the study described in Chapter 9, the correlogram gives the impression that changes in ESR precede changes in joint
pain score. Note that other measures for the reduction of the 24 h ambient temperature and humidity were in effect as well: not wearing pyjamas and keeping the bedroom window open (since 1984), and not
wearing a coat outdoors at temperatures above 0 °C (since 1992).
Chapter 11 General discussion 122
In a study like this, research and therapy go hand in hand. A rigid experimental protocol will give clear and quick results but may lead to
worsening of the patient's situation. For instance, staying indoors for a
long period might show a clear increase in ESR, CRP, and RF values,
along with an increase in pain. Scientifically, this would be a valuable
observation but ethically it is not acceptable. However, the lack of effects of long-lasting periods with daily very short time spent outdoors is
somewhat compensated by the effects found during a few short periods
in which the patient hardly was outdoors (January-April 1997, OctoberNovember 1997, and November 1998-January 1999). In all these periods there was a clear increase in joint pain score, ESR, CRP, and RF.
As shown in Figure 1, medication was stable during all these periods.
0.2
correlation coefficient
0.1
0
-0.1
-0.2
-0.3
-0.4
-200
-150
-100
-50
0
50
100
150
200
phase shift (days)
Cross correlation of the ESR () as well as daily joint pain score () with the daily time
spent outdoors during 7 years (1997-2003). The minimum in correlation coefficient was 0.30 (P<0.01) for the correlation between time outdoors and the pain score at a phase shift
of 32 days. This indicates that changes in time spent outdoors are about 1 month later
followed by opposite changes in pain score. The changes in ESR seem to be less delayed,
although the minimum in correlation coefficient is not very clear.
Microclimate
The results of many studies on effects of the weather on RA can be explained best by assuming a positive relationship between RA variables
and the humidity of the microclimate close to the patient’s skin. This is
the conclusion of the review described in Chapter 2. In addition to the
outdoor humidity, the humidity of the microclimate is influenced by
housing, clothing, air conditioning, etc. This is illustrated in Figure 3. In
general, the indoor humidity is higher than outdoors due to several
sources of water vapor, like cooking, bathing, respiration, especially
when ventilation is poor (Figure 3, filled circles). The humidity of the
microclimate is still higher due to water evaporation through the skin
even if no sweating occurs.
Chapter 11 General discussion 123
Figure 2
vapor pressure
(g water/kg dry air)
20
15
10
5
0
aug
2003
sep
okt
nov
dec
jan
2004
feb
mrt
apr
mei
jun
Figure 3 Course of the 24 h mean vapor pressure measured outdoors (solid line), in the ambient air
on the clothes (filled circles), and in the microclimate at the skin (open circles) of the
author living at Groningen, The Netherlands. Outdoor vapor pressures were calculated
from the outdoor temperature and relative humidity data supplied by the Royal Dutch
Meteorological Institute (KNMI) for the location Groningen Airport. Temperature and
relative humidity data for the calculation of the vapor pressure of the ambient air and the
microclimate were obtained using a data logger (Gemini Data Loggers, Tiny Tag Ultra
TGU-1500; 10 minutes measuring interval). From August 2003 till February 2004, the
data logger was worn on the skin of the chest as a necklace (at night fixed to the quilt
cover facing the skin), and from February till June 2004 attached to the belt (at night fixed
on top of the quilt cover).
Chapter 11 General discussion 124
The difference in humidity between the microclimate and the air outdoors is very small in August (light clothing, open windows, more living
outdoors) and it increases in the colder months (Figure 3, open circles).
The increase of the humidity of the microclimate, caused by more
clothing is considerable (Figure 3, compare open and filled circles in
February 2004). Note that in the cold months, the humidity of the microclimate is almost twice as high as the outdoor humidity. These data
support the conclusions of the above-mentioned review (Patberg &
Rasker, 2004). It is remarkable that the correlation of the daily joint pain
score with the vapor pressure of the microclimate is stronger (r: 0.25,
P<0.05) than that with the outdoor vapor pressure (r: 0.17) (Figure 4, cf.
correlation coefficients at phase shift 1 day). This supports the hypothesis that the humidity of the microclimate influences the disease activity.
Initially, the purpose of spending more time outdoors was to reduce the
mean temperature and humidity of the ambient air. Having found subsequent beneficial effects on my disease, I became more convinced that
there is a relationship between the daily means of these variables and
the variables of my RA. Later, I realized that staying outdoors for e.g. 3
hours, in which the vapor pressure of the microclimate is reduced e.g.
from 8 to 4 g water/kg dry air, will decrease the 24 h mean vapor pressure of the microclimate from 8 to only 7.5 g water/kg dry air. This
change is negligible with respect to the fluctuations shown in Figure 3.
The same reasoning is applicable for the temperature of the microclimate. Therefore, I consider the actual situation during the stay outdoors, with strong decreased vapor pressure and temperature, to have
an effect, not the change in the 24 h mean values.
0.4
0.3
correlation coefficient
* *
* *
0.2
0.1
0
-0.1
-0.2
-0.3
-14
-7
0
phase shift (days)
7
14
Figure 4 Cross correlation of the daily joint pain score with the outdoor vapor pressure (), and the
vapor pressure of the microclimate () (August 2003-February 2004). On days when the
mean vapor pressure of the microclimate was not available, the corresponding data of the
outdoor vapor pressure were discarded in order to keep the correlograms comparable. At a
phase shift of +1 day (vapor pressure preceding the pain score) the correlation coefficient
higher than the relation with the outdoor vapor pressure (*: P<0.05).
As mentioned, about half the time spent outdoors, I was cycling, mostly
without a coat. Therefore, it might be argued that the exercise, rather
than the weather has caused the beneficial effect. However, observations
in the summers of 1995 and 1997 refute this: the disease activity (Figure
1: CRP, ESR, and joint pain score) did increase with increasing temperature and vapor pressure although about 3 hours were spent outdoors daily. Not until the decrease in temperature and vapor pressure at
the end of the summer (1997), the disease activity decreased.
Chapter 11 General discussion 125
of the relation of the pain score with the vapor pressure of the microclimate is clearly
One subject
Except those described in Chapters 2, and 6, the studies were all done on
one and the same patient. Therefore, this thesis should be considered as
a report of a comprehensive pilot study. In order to answer the question
“How common are beneficial effects of being outdoors in RA patients?”
plans are made to repeat the study done on myself, on 30 other patients
with RA. There are several reasons to assume that the reported results
do not belong to a unique case:
- The effect of the weather on the daily joint pain score of myself is
comparable with that on the daily mean score of 88 RA patients in an
earlier study (Chapter 6).
- In personal reactions on publications of my studies, many RA patients
declared that they had experiences similar to those I had reported.
- The most recent review of the literature on weather effects on RA concluded that there is a relationship between RA complaints and the
humidity of the microclimate at the patient’s skin (Chapter 2). Hence,
the increased ventilation of the microclimate when staying outdoors
may be expected to be beneficial to other RA patients as well.
- Even the statement of RA patients that they feel better on holidays in a
warm country is in accordance with my own experiences. Although
the temperature and vapor pressure are rather high, people will be
outdoors almost all day, and wear only few clothes. Therefore, the vapor pressure at the skin will not build up.
Conclusions
Chapter 11 General discussion 126
The primary aim of the studies in this thesis was to explore whether the
variations in the disease activity of my own RA were related to “whatever”, and if so, whether it is possible to manipulate that “whatever” in
order to suppress the disease activity as much as possible. Probably,
there are several “whatevers” influencing the disease, but one of these is
associated with the temperature/humidity complex of the microclimate.
There are many possibilities to manipulate this complex, i.e. making the
microclimate cooler and less humid, which after some delay, turned out
to decrease the disease activity. The effect is reversible, so for a prolonged beneficial effect, the manipulation of the microclimate needs to
become a daily routine. Due to this reversibility it is possible that the
objective RA variables ESR, and CRP in general did not significantly
decrease. The slightly lower level of these variables since 2000 (Figure 1)
should be attributed rather to the medication than to being outdoors.
However, the relation between being outdoors and the RF is significant,
and the gradual decrease of the RF since spring 2002 is likely to be associated with the, in general, long time that was spent outdoors daily.
Several factors may have caused the low level of the joint pain score in
the later years: the medication, joint surgery, and even psychological
factors. In addition to this, the many hours that I have spent outdoors
have had a favorable influence on the pain score as has been illustrated
above (Figure 2).
Underlying mechanism
The underlying mechanism is unknown. The words of the British physician, and discoverer of argon, John W. Strutt (Baron Raleigh, 18421919) nicely express how hard it is to imagine that changes in humidity
of the air can have effect on the human body: “I cannot conceive why
we who are composed of over 90% water should suffer from rheumatism with a slight rise in the humidity of the atmosphere”.
Future research
Suggestions for further investigations on the relationship between the
microclimate and RA variables are given in Chapter 2. Of course the
next question to be answered is “How common are the beneficial effects
of being outdoors in RA patients?” The results found on myself justify a
study on other patients with RA. Depending on the results of the abovementioned project on 30 patients, measures taken to decrease the humidity of the microclimate might become advisable for patients with
RA.
Chapter 11 General discussion 127
Perhaps, evaporation by the skin plays a role; this will increase when the
microclimate becomes less humid. It is possible that spending more time
outdoors, which is more or less experienced as physical stress, stimulates the production of cortisol with subsequent suppression of inflammation in the joints. The use of alcohol would inhibit this influence by
its lowering effect on the production of cortisol (Chapter 10). In a future
study it would be interesting to investigate whether a period in which 3
hours are spent outdoors daily, will increase the cortisol level.